Senescent astrocytes and microglia, which accumulate with age and in patients with AD, contribute to neurodegeneration. A major gap in our knowledge is understanding the mechanisms that lead to astrocyte senescence. Our long-term goal is to define the molecular targets and therapeutic interventions that slow aging by inhibiting senescence and to determine their impact on neurodegenerative diseases. The overall objective in this application is to: 1) define the mechanisms by which the glycolytic by-product methylglyoxal (MGO) drives astrocyte senescence and 2) enhance the detoxification of MGO to mitigate astrocyte senescence and neurodegeneration in models of AD. Our central hypothesis is that MGO induces senescence in astrocytes, which secrete pro-inflammatory senescence-associated secretory phenotype (SASP) factors that cause the neurodegeneration associated with dementia and AD. The rationale of our hypothesis is based partly on the fact that astrocytes are known to be the metabolic workhorses of the brain and undertake glycolysis to provide neurons with lactate. Consequently, astrocytes produce more MGO and show increased activity of the MGO detoxifying pathways. We observe that MGO, which enhances macromolecular damage, causes senescence. Thus, strategies to detoxify MGO can provide novel approaches to lowering the risk of AD and related neurodegeneration in the elderly. We will test the hypothesis by pursuing the following Specific Aims: 1). Determine the mechanisms by which MGO drives senescence in human iPSC derived astrocytes; 2) Determine the mechanisms by which senescent astrocytes cause neuronal damage; and 3) Determine the role of the Trpa1 pathway in modulating MGO-induced senescence and AD pathology in mouse models. We will use iPSC derived astrocytes to determine the mechanisms by which MGO mediates senescence. Furthermore, we will use proteomics to define the SASP of MGO-induced senescent astrocytes and determine the effect of the SASP on iPSC-derived neurons carrying wild type and mutant alleles of tau using co-cultures. We will genetically and pharmacologically manipulate Trpa1 to detoxify MGO to test its effects on senescence and associated neurodegeneration in two mouse models of AD. We will combine the treatments to detoxify MGO and eliminate senescent cells to determine if they are working through the same pathways to inhibit neurodegeneration. The proposed research is innovative because it will determine a novel function for MGO, an endogenous metabolite produced during glycolysis, in driving astrocytic senescence and, thus, neurodegeneration. A key significance of this work will help us understand the link between metabolism, inflammation, and neurodegeneration. It will also pave the way to developing novel therapies for treating Alzheimer?s and related dementias based on reducing the presence or activity of senescent cells and by lowering MGO.